SENEXPACE

Fibroblast Growth Factor 21 (FGF21) is a crucial protein involved in regulating cellular processes associated with ageing. It is produced in response to stressors such as DNA damage, mitochondrial dysfunction and oxidative stress, reflecting the activation of protective cellular mechanisms. FGF21 is secreted as an adaptive response, promoting mitophagy to eliminate damaged mitochondria and preserve cellular quality. This function is particularly essential in tissues with high energy demands, where mitochondrial dysfunction accelerates functional decline.

FGF21 is considered a marker of cellular senescence, a condition characterised by the permanent arrest of cell proliferation and the secretion of inflammatory mediators, which is closely linked to ageing and chronic diseases. It increases in the presence of DNA damage, regulating cell cycle arrest and autophagy to limit the accumulation of mutated cells. However, chronic expression may stabilise senescence, aggravate genomic instability and promote irreversible damage.

The senescence-associated secretory phenotype (SASP) promotes low-grade chronic inflammation (inflammaging). FGF21 can modulate this state: in the acute phase, it reduces inflammation and improves metabolism, but chronic expression favours a pro-inflammatory environment that accelerates ageing and increases the risk of degenerative diseases.

Plasma levels of FGF21 rise with age, making it a useful biomarker for identifying cellular senescence and metabolic dysfunction. Its dual role—protective in acute stress but pro-senescent in chronic conditions—highlights the complexity of its functions. FGF21 contributes to the protection of healthy tissues, but if overexpressed, it promotes the systemic decline associated with ageing.

Glial Fibrillary Acidic Protein (GFAP) is a structural protein, whose primary role is to support the shape, mechanical integrity, and stability of cells and tissues. It plays an essential role in the construction and maintenance of biological architecture, serving as a key component in forming resilient, elastic, or dynamic structures. GFAP is mainly expressed by astrocytes and plays a vital role in the central nervous system’s (CNS) response to cellular injury and neurological stress.

GFAP levels are closely associated with genotoxic processes and genomic instability, conditions that characterise many neurodegenerative diseases, brain injuries and ageing. Its regulation is directly implicated in the health of neural stem cells (NSCs), influencing neurogenesis and brain function.

GFAP is expressed in response to various cellular stressors, including DNA damage, oxidative stress, and mitochondrial dysfunction. However, chronically elevated levels may promote the accumulation of genomic damage, interfere with DNA repair mechanisms and contribute to a pro-mutagenic cellular environment.

Mutations in the GFAP gene or epigenetic alterations leading to mutated variants of the protein compromise DNA repair capacity, accelerate neuronal decline and contribute to the development of neurodegenerative diseases.

A major factor in the increase of GFAP levels is mitochondrial dysfunction, where the rise in reactive oxygen species (ROS) production stimulates GFAP expression as an adaptive response. However, the accumulation of dysfunctional mitochondria intensifies oxidative stress and accelerates brain deterioration, fuelling a vicious cycle that contributes to the progressive decline of brain tissue during ageing.

GFAP is essential for maintaining the environment of neural stem cells (NSCs), promoting neurogenesis through astrocytic activity. However, excessive GFAP production due to astrocyte hyperactivation disrupts this balance, reducing NSC regenerative capacity and impeding the formation of new neurons.

These effects are amplified with ageing and in neurodegenerative diseases, resulting in a loss of brain plasticity—i.e., the brain’s capacity to adapt and recover from damage. The increase in GFAP in senescent astrocytes is associated with the release of pro-inflammatory cytokines such as IL-6 and TNF-α, which intensify neuroinflammation and exacerbate neural damage. In conditions such as Alzheimer’s, Parkinson’s and multiple sclerosis, the accumulation of senescent astrocytes with high GFAP levels amplifies neuronal damage and accelerates disease progression. Therefore, GFAP is not only an indicator of pathological processes but also a contributor to brain deterioration, making it a potential target for therapeutic interventions. Persistent elevation of GFAP compromises neurogenesis, leading to reduced brain plasticity and cognitive decline associated with ageing. In pathological conditions like Alzheimer’s and multiple sclerosis, elevated GFAP expression worsens age-related neuronal decline.

GFAP is more than a marker of cellular stress: it plays a central role in the brain’s response to damage, genotoxicity, and inflammation. Its involvement in regulating the neural stem cell environment, neurogenesis, and inflammatory processes highlights its importance for brain health. Although crucial in responding to acute stress, chronically elevated GFAP contributes to neuroinflammation, loss of brain plasticity, and the progression of neurodegenerative diseases.

Understanding GFAP regulatory mechanisms opens new avenues for developing therapies aimed at slowing brain ageing, improving quality of life, and intervening in neurodegenerative disorders by promoting regeneration and resilience of the central nervous system.

Neurofilament Light Chain (NFL) is a structural neuronal protein essential for cytoskeletal stability. Under conditions of oxidative stress and neuroinflammation, NFL is released into the bloodstream and cerebrospinal fluid, thus serving as a biomarker of neuronal damage and genotoxicity (i.e., DNA damage and impairment of repair mechanisms).

Oxidative stress caused by the accumulation of reactive oxygen species (ROS) damages cytoskeletal proteins like NFL and amplifies DNA damage. Chronic neuroinflammation, associated with increased ROS and reactive nitrogen species, worsens the pro-inflammatory microenvironment and impairs cellular repair mechanisms, promoting genomic instability.

Elevated levels of NFL in blood or cerebrospinal fluid are a reliable indicator of neuronal damage, genomic instability, and neurodegenerative or ischaemic conditions. Its monitoring allows the evaluation of disease progression and the effectiveness of therapies aimed at reducing oxidative stress and improving genomic stability.

NFL dysregulation negatively affects stem cells, significantly contributing to their dysfunction. Altered NFL levels are associated with a chronic pro-inflammatory microenvironment, which, through increased inflammatory cytokines and ROS, damages the stem cells themselves.

This process accelerates stem cell ageing and limits tissue regenerative capacity. Persistently damaged stem cells enter a state of senescence, halting the cell cycle and losing regenerative ability. Additionally, the accumulation of DNA damage compromises their regenerative plasticity, reducing differentiation potential and leading to functional tissue decline.

Impaired stem cell regenerative capacity renders organs less effective in damage repair and cellular turnover, leading to typical signs of ageing, such as muscle frailty, skin elasticity loss and cognitive decline. Moreover, damaged stem cells perpetuate inflammation by secreting pro-inflammatory factors, accelerating tissue degeneration.

NFL alteration is associated with an increased risk of age-related diseases such as neurodegenerative disorders (e.g., Alzheimer’s and Parkinson’s), cardiovascular diseases, and cancer. Genomic instability caused by NFL fragmentation impairs DNA repair and favours neoplastic transformation, increasing susceptibility to malignant diseases.

Growth Differentiation Factor 15 (GDF15) is a key protein in the processes of inflammation, metabolic regulation, cell growth and tissue damage response. Its expression rises significantly in conditions of cellular stress, mitochondrial dysfunction and DNA damage, and it is therefore considered a biomarker of cellular senescence. GDF15 reflects the accumulation of senescent cells and highlights their impact on the organism, making it useful for diagnosing and monitoring ageing-related diseases and evaluating therapeutic interventions.

GDF15 acts as a sensor and modulator of cellular responses to oxidative stress and DNA damage, establishing a link with genotoxicity and genomic instability. Increased expression represents a protective strategy to limit the proliferation of damaged cells and promote DNA repair. However, excessive responses may reduce stem cell proliferative capacity, impair tissue renewal, and increase vulnerability to conditions such as cancer and neurodegenerative diseases.

Elevated levels of GDF15 may impair the proliferation of stem cells, which are essential for tissue maintenance and regeneration. This inhibition reduces the pool of active stem cells, accelerating ageing processes. GDF15 modulates responses to oxidative stress and inflammation, both of which are closely linked to genotoxicity and functional decline associated with ageing.

In conditions of cellular damage or chronic stress, increased GDF15 negatively impacts stem cells, altering the balance between quiescence and activation. This may induce a prolonged state of inactivity or lead to early exhaustion of stem cells, limiting their capacity for tissue renewal and impairing long-term regeneration.

GDF15 expression increases in response to DNA damage caused by ionising radiation, genotoxic agents or oxidative stress, reflecting a protective mechanism intended to limit the proliferation of damaged cells. With ageing, its systemic levels progressively rise, correlating with the accumulation of senescent cells and the progression towards chronic diseases. Plasma GDF15 measurement can signal the presence of senescent cells and the risk of developing cardiovascular, metabolic, or neurodegenerative diseases, making it a prognostic marker in several conditions.

GDF15 represents a potential therapeutic target to modulate the adverse effects of senescence and chronic inflammation. Furthermore, it acts as a “molecular alarm”, promoting DNA repair or the elimination of irreparably damaged cells, thus protecting the body from further pathological consequences.